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Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that patrol tissues to sense danger signals and activate specific immune responses. In addition, they also play a role in inflammation and tissue repair. Here, we show that oxygen availability is necessary to promote full monocyte-derived DC differentiation and maturation. Low oxygen tension (hypoxia) inhibits expression of several differentiation and maturation markers (CD1a, CD40, CD80, CD83, CD86, and MHC class II molecules) in response to lipopolysaccharide (LPS), as well as their stimulatory capacity for T-cell functions. These events are paralleled by impaired up-regulation of the chemokine receptor CCR7, an otherwise necessary event for the homing of mature DCs to lymph nodes. In contrast, hypoxia strongly up-regulates production of proinflammatory cytokines, particularly TNFalpha and IL-1beta, as well as the inflammatory chemokine receptor CCR5. Subcutaneous injection of hypoxic DCs into the footpads of mice results in defective DC homing to draining lymph nodes, but enhanced leukocyte recruitment at the site of injection. Thus, hypoxia uncouples the promotion of inflammatory and tissue repair from sentinel functions in DCs, which we suggest is a safeguard mechanism against immune reactivity to damaged tissues.

Original publication

DOI

10.1182/blood-2008-02-142091

Type

Journal article

Journal

Blood

Publication Date

01/11/2008

Volume

112

Pages

3723 - 3734

Keywords

Animals, Cell Differentiation, Cell Hypoxia, Cells, Cultured, Chemokines, Chemotaxis, Cytokines, Dendritic Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation, Ligands, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Monocytes, RNA, Messenger, Toll-Like Receptors